C. elegans for the discovery of new anthelmintics compounds present on essential oils

HERNANDO, G.; TURANI, O.; BOUZAT, C.

Los Angeles, CA and Online Anywhere and Everywhere

Conferencia; 23rd International C. elegans Conference Online; 2021

Genetics Society of America (GSA)

Helminths consist of a diverse group of parasitic worms including nematodes, these infect a significant proportion of persons living in resource poor regions and cause diseases of major socio-economic importance globally to both humans and animals. Worldwide, helminth infections of the gastrointestinal tract are most common (Ascaris sp, Trichuris sp), but other nematodes have blood, skin or muscle stages. Control of infections in both human and veterinary medicine currently relies mainly on chemotherapy, but resistance is an increasing problem, so there is an urgent need for discovery of novel drugs. As parasitic nematodes are not ideal laboratory animals, the free-living nematode C. elegans was demonstrated to be an excellent model system for the discovery of new anthelmintics and for characterizing their mechanisms of action and resistance. Essential oils (EOs) are natural products produced by aromatic plants. EOs are complex mixtures that contain 2 or 3 major phytochemicals, which can be terpenes or aromatic compounds. We used paralysis assays of wild-type and mutant C. elegans strain to identify EOs with potential anthelmintic activities, reveal the active components, the target sites and the mechanisms of action. We found that EOs belonging to six different orders produced rapid paralysis of C. elegans and we established the half maximal effective concentration values between 0.02-1.2 percent of EOs. All EOs tested also inhibited egg hatching, a property related to anthelmintic ability. Thus, EOs mediate both rapid and long-term anthelmintic effects. We determined that trans-cinnamaldehyde (TC), a major component of C. verum EOs, produces both paralysis and egg-hatching inhibition. By testing mutant worms, we identified the muscle L-AChR and GABA receptors as EOs and TC targets in vivo. Thus, by modulating two receptors with key roles in worm motility, these EOs emerge as novel sources of anthelmintic compounds. Likewise, the N-AChR mutant strain is slightly resistant to TC, thus revealing a third target receptor for terpenes. Due to the potential of EOs as sources of novel antiparasitic compounds, additional studies will be carried out to determine in more detail the molecular mechanisms of action and structure-activity relationships of their active compounds. It is hoped that this work can update the recent progress on natural nematicide discoveries and provide new ideas for the design and mechanism of action studies of anthelmintics.